The group of pathologies produced by a lack of activity in some of the enzymes of the heme group biosynthesis is generically known as porphyria. Normally the loss of activity is produced by mutations in the amino acid sequence of said proteins and the type of porphyria depends on the specific enzyme causing the mutation. The heme group biosynthesis is shown in scheme 1 indicating the enzymes involved in each stage of the pathway (above the reaction arrow) and detailing the names of the specific pathologies caused by functioning deficiencies in each of these enzymes (below the reaction arrow) [P=propionate, A=acetate, V=vinyl, M=methyl].

Congenital erythropoietic porphyria (CEP) also known as Günther's disease named after the author who described it in 1911, is a hereditary disease and the least frequent of the porphyrias. This disease is a consequence of a malfunction in the uroporphyrinogen III synthase (UROIIIS), which is an enzyme of 260 residues (in the human isoform) catalyzing the cyclization of the linear tetrapyrrole hydroxymethylbilane to produce macrocycle uroporphyrinogen III (or urogen III), the precursor of the heme groups, siroheme, F340, vitamin B12 and chlorophyll. The tetrapyrrole substrate is highly unstable and in the absence of the UROIIIS enzyme it spontaneously degrades to uroporphyrinogen I (uroporphyrinogen I and III differ only in the position of a P group and an A group in the D ring of the cycle). The cyclization of the preuroporphyrinogen for producing uroporphyrinogen III (enzymatic pathway) or uroporphyrinogen I (spontaneous degradation) is shown in scheme 2.

Uroporphyrinogen I and its derivatives are difficult to catabolize byproducts that tend to accumulate in the body. Thus, large amounts of uroporphyrinogen I which accumulate in bags below the eyes and deform the extremities are produced in CEP patients (those having a UROIIIS deficiency). Depending on its severity, other common symptoms of the disease are, for example, an extreme sensitivity to sunlight from infancy that manifests as intense dermal lesions in the exposed areas, bone and cartilage destruction, erythrodontia (dark brown coloration of the teeth, especially baby teeth due to the porphyrin accumulation), anemia, etc.
Today, the only curative treatment for CEP is a bone marrow transplant, i.e., replacing the bone marrow of the CEP patient (recipient) with the healthy bone marrow of another person (donor). After an effective transplant the clinical characteristics of CEP, such as photosensitivity or anemia are resolved. However, the scars from previous skin lesions are permanent. Furthermore, for a successful transplant the bone marrow of the donor must have high similarity to that of the recipient. In this sense, the bone marrow transplant is a high-risk treatment and powerful treatments inhibiting the recipient's immune system are initially required to prevent rejection. Due to all of this, a bone marrow transplant is reserved for those severely affected individuals having an identical bone marrow donor.
Therefore to this day, the treatment of CEP is only limited to attempting to prevent or relieve its symptoms, such as for example, by using sunscreens to prevent skin and eye scars, the continuous administration of heme derivatives or transfusing blood to counteract heme group deficiency, etc.
Although the inhibition of porphobilinogen deaminase (PBGD; the enzyme also known as hydroxymethylbilane synthase or uroporphyrinogen I synthase) would imply the reduction of the amount of preuroporphyrinogen and therefore an improvement of life conditions for CEP patients, all the studies performed in this sense up until now have been unfavorable. The PBGD enzyme has been subjected to an intense mechanistic study [Louie G V et. al. (1992) Nature 359: 33-39; Jordan P M, Woodcock S C (1991) The Biochemical journal 280 (Pt 2): 445-449]. The identification of the substrate binding site has involved the development of “suicidal” inhibitors (that covalently bind to the enzyme and prevent the progression of the reaction). It particularly relates to derivatives of the enzymatic substrate such as 2-bromoporphobilinogen [Battersby A R (2000) Natural product reports 17: 507-526; Jones R M, Jordan P M (1994) The Biochemical journal 299 (Pt 3): 895-902; Warren M J, Jordan P M (1988) Biochemistry 27: 9020-9030] or 6-methylporphobilinogen and 6,11-ethanoporphobilinogen [Ahmed R, Leeper F J (2003) Org Biomol Chem 1: 21-23]. It has also been found that porphyrins can inhibit enzyme [Araujo L S et. al. (1994) Int J Biochem 26: 1377-1381]. Despite their specificity, their efficiency as in vivo inhibitors has not been demonstrated, and their high reactivity rules them out as potential drugs. In fact, it would be expected that these porphobilinogen derivatives generate many problems in vivo as they bind covalently to the enzyme and permanently inactivating it. Furthermore, the substrate is a secondary metabolite and therefore analogous inhibitors thereof could have inhibitory activity on other enzymes reducing the in vivo selectivity.
Given that there is a cysteine involved in the catalysis mechanism, PBGD protein modifying agents have also been studied. It has been found that some substances such as metal ions or 2-mercaptoethanol can significantly alter the catalytic activity of the porphobilinogen deaminase of Arabidopsis thaliana [Jones R M, Jordan P M (1994) The Biochemical journal 299 (Pt 3): 895-902]. However, this is due to a non-specific chemical modification mechanism of the enzyme and not due to a specific binding of the molecule in the active site of the protein. Likewise, the studied model is being questioned since a low inhibition by N-ethylmaleimide is seen, while the same reactant strongly deactivates the Escherichia coli enzyme [Warren M J, Jordan P M (1988) Biochemistry 27: 9020-9030]. The complete list of tested substances can be found in the database Brenda: http://www.brenda-enzymes.org/php/result flat.php4?ecno=2.5.1.61
In view of aforementioned, there is still a need of providing therapeutic agents with inhibitory capacity to inhibit the catalytic activity of porphobilinogen deaminase potentially useful in the prevention and/or treatment of congenital erythropoietic porphyria (CEP). In addition to being effective, said compound inhibitors advantageously should not cause undesirable toxicity. Likewise, from their synthesis point of view and pharmacological screening point of view, it would be highly desirable that the compounds can be easily modulated.